Amides in One Pot from Carboxylic Acids and Amines via

Letter pubs.acs.org/OrgLett

Amides in One Pot from Carboxylic Acids and Amines via Sulfinylamides Jianfei Bai,‡ Bartosz K. Zambroń,‡ and Pierre Vogel* Laboratoire de Glycochimie et de Synthèse Asymétrique, Swiss Federal Institute of Technology (EPFL), Batochime, CH 1015 Lausanne, Switzerland S Supporting Information *

ABSTRACT: An efficient method has been developed for the direct amidification of carboxylic acids via sulfinylamides preformed in situ by the reaction of pure amines with prop-2ene-1-sulfinyl chloride. The method can be applied to aliphatic acids, including pivalic acid, aromatic acids, and primary and secondary amines. It is compatible with acids bearing unprotected alcohol, phenol, and ketone moieties and applicable to the synthesis of peptides. It does not induce their α-epimerization.

A

Scheme 2. Activation of Carboxylic Acids and Amines by the Sulfinyl Group

mide formation from carboxylic acids and amines is a fundamental reaction in organic, biological, medicinal, polymer, and material chemistry for which a great amount of research is still pursued.1 Most methods rely upon nucleophilic addition of the free amines onto an activated acyl compound derived from the carboxylic acid.2 We report here a new approach that relies on activation of amines 1 in the form of sulfinyl amides.3,4 Under high temperature microwave conditions, isonitriles react with carboxylic acids to give carboxamides.5 Thioacids have been reacted with isonitriles,6 isocyanates,7 azides,8 and amides.9 The main challenge is to find mild reaction conditions that avoid α-epimerization of the carboxylic acids and of the corresponding carboxamides and that tolerate other unprotected functions or functions protected adequately for further use of the carboxamides in fine synthesis. This is the case with our new method (Scheme 1), as neither a strong base nor acid

reaction (Scheme 2, eq 3) should equilibrate sulfinylamides and carboxylic acids with carboxamides and sulfinyl acids. It could be a useful route for the direct amidification of carboxylic acids, as sulfinyl amides are readily available.10 Our exploratory studies started with the reaction of ptoluenesulfinylamide11 5aa and 3-phenylpropionic acid 3A (Scheme 3). Using a 0.1 M solution of 3A and 5aa in MeCN a Scheme 3. Sulfinyl-Carbonyl Exchange Reactions

Scheme 1. General Method of One-Pot Direct Amidification of Carboxylic Acid

is required. Furthermore, purification of the carboxamides is facilitated by the fact that the coproducts of the reaction are Et3NH+Cl− and volatile propene and SO2, and only a 20% excess of acid is used. Recently we reported that mixed anhydrides of sulfinyl and carboxylic acids (sulfinyl carboxylates: RS(=O)−O−COR3) react at 20 °C with all kinds of nucleophiles including primary and secondary amines at sulfur exclusively in the reaction (Scheme 2, eq 1), unless steric hindrance (R: CH2CH− CMe2) permits the addition to the carbonyl group to compete, and also with amines, to generate the corresponding carboxamides as in the reaction (Scheme 2, eq 2).2 The related © XXXX American Chemical Society

slow reaction was observed at 70 °C giving the expected carboxamide 4aA and p-toluenesulfinic acid 6a. DMAP (4dimethylaminopyridine) accelerated the reaction. With 0.2 equiv of DMAP at 70 °C a half-life of 8 h was evaluated by 1H NMR. The rate enhancement induced by 0.2 equiv of DMAP was ca. 5-fold. As we thought that the addition of 3A to the Received: December 4, 2013

A

dx.doi.org/10.1021/ol403508j | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

sulfinyl amide could be accelerated by increasing its electrophilicity, we explored the reaction of pyrrolidine p-nitrobenzenesulfinyl amide12 with 3A. To our surprise no trace of carboxamide 4aA did form after prolonged heating to 70 °C, in the absence or in the presence of 1 equiv of DMAP. Similarly, no reaction could be observed under the same reaction conditions with pyrrolidine trifluoromethanesulfinyl amide13 and pyrrolidine isobutyronitrilesulfinyl amide.14 On heating carboxamide 4aA to 70 °C with CF3SO2H, with or without DMAP, no sulfinyl/carbonyl exchange could be seen. The reactions of 3A with methanesulfinyl amide 5ab15 and prop-2enesulfinyl amide 5ac16 (0.2 equiv of DMAP as the catalyst) at 70 °C were faster than with p-toluenesulfinyl amide 5aa under the same conditions and gave carboxamide 4aA. Half-lives of 4 and 1 h were evaluated for reactions 3A + 5ab and 3A + 5ac, respectively. The two latter reactions are ca. twice and 8 times, respectively, as fast as reaction 3A + 5aa. Upon prolonged heating of 3A with 5ab full conversion of 5ab was reached after 6 h and 4aA was isolated in 74% yield only. After 1 equiv of Et3N was added to neutralize MeSO2H 6b formed as the coproduct, the yield of pure 4aA increased to 90%. In a parallel experiment we demonstrated that MeSO2H induces the slow decomposition of 5ab. With sulfinyl amide 5ac no base is required to neutralize the sulfinic acid formed, as the latter (prop-2-enesulfinic acid, 6c) undergoes a quick retroene reaction at 70 °C with formation of volatile propene and SO2.17 When using a 20% excess of the carboxylic acid 3A and 20 mol % of DMAP, the medium never becomes basic or acidic as verified for aliquots mixed with water (pH 4.5 to 3.5). Most importantly, the amidification yield was the highest for reaction 3A + 5ac. As electron-poor sulfinylamides failed to produce carboxamides, we explored the reaction of 3A with electron-rich sulfinylamides 5ad, 5ae, and 5af. They all produced carboxamide 4aA but more slowly than reaction 3A + 5ac. Carboxylic acids 3B−3T were then reacted with 5ac. The results are summarized in Table 1. Except for 4-p-dimethylaminobenzoic acid all the reactions produced the expected carboxamides (Table 1). Linear and αmonobranched aliphatic carboxylic acids reacted the quickest and led to good yields of the corresponding amides. Pivalic acid 3I reacted more slowly and gave amide 4aI after 32 h at 70 °C in an acceptable yield of 57%. Benzoic acids reacted more slowly than cyclopentanecarboxylic acid 3S. Better yields were obtained with electron-poor benzoic acid derivatives 3J, 3K than with electron-rich ones 3M, 3N. However, o-hydroxybenzoic acid 3L led to a good yield of 4aL. Most interesting is the observation that our reaction conditions are compatible with the presence of unprotected alcohol, phenol, and ketone moieties. With (S)-phenylsuccinic acid 3T a 1:2 mixture of monoamides 4aT + 4aT′ formed (1H NMR). The same occurred when mixing pyrrolidine 1a (1.0 equiv) with phenylsuccinic anhydride. We then generated propene-2-sulfinyl amides from piperine 1b, benzyl amine 1c, aniline 1d, (S)-1-methylbenzylamine 1e, tert-butyl ester of L-valine 1f, and L-proline 1g and reacted them with a large variety of carboxylic acids 3 including N-protected α-amino acids. All the reactions produced the expected carboxamides in good yields (not shown). As we found that Et3NH+Cl− does not perturb the reactions of sulfinylamide 5ac with acids 3, we developed a one-pot, direct amidification of carboxylic acids. Our results are summarized in Table 2 (for more examples, see Supporting Information). The method is successful for primary and secondary amines. It did not work

Table 1. Amidification of Carboxylic Acids with Sulfinylamide 5aca R3COOH, 3

4a

time (h)

yield (%)

PhCH2CH2CO2H, 3A PhCH2CO2H, 3B PhCO2H, 3C PhCOCH2CH2CO2H, 3D (E)-PhCHCHCO2H, 3E 2-OH-C6H4CH2CO2H, 3F (S)-mandelic acid, 3G (S)-lactic acid, 3H t-Bu-CO2H, 3I 4-NO2-C6H4CO2H, 3J 4-CF3-C6H4CO2H, 3K 2-OH-C6H4CO2H, 3L 4-CH3O-C6H4CO2H, 3M 4-Me2N-C6H4CO2H, 3N 3-(3-pyridinyl)propionic acid, 3Ob (E)-3-(2-thienyl)acrylic acid, 3P Isobutyric acid, 3Q n-Pent-CO2H, 3R c-Pent-CO2H, 3S (S)-phenylsuccinic acid, 3T

4aA 4aB 4aC 4aD 4aE 4aF 4aG 4aH 4aI 4aJ 4aK 4aL 4aM 4aN 4aO 4aP 4aQ 4aR 4aS 4aT

6 6 12 6 8 6 8 8 32 10 8 8 48 48 6 10 6 6 6 3

94 90 88 89 85 90 85 75 57 77 73 78 50 0. 83 81 82 81 82 76

a Conditions: 5ac (0.75 M)/3/DMAP (1:1.2:0.2) in MeCN at 70 °C. Yield of amide 4 after workup. DMF (5−10% v/v) was added when the acid was not completely soluble in CD3CN.

with indole which is sulfinylated at C3 with prop-2-enesulfinyl chloride 2c (not shown). Using tert-butyl esters of L-valine 1f and L-proline 1g as amines and benzyl carbamates of glycine 3U, L-proline 3V, and L-valine 3W as acids, the six protected dipeptides 4fU, 4gU, 4fV, 4gV, 4fW, and 4gW were obtained. The 1H and 13C NMR spectra of concentrated solutions of compounds 4eV, 4eW, 4fV, 4fW, 4gV, and 4gW (with two stereogenic centers) did not show any detectable α-epimerization (comparison with the spectra of amides made from racemic valine and proline). The 100 °C 1H NMR spectra of 4eV and 4eW showed smaller signals for the methyl group of diastereomeric amides than the 13 C-satellites of the methyl signals of these compounds. In these two cases, if α-epimerization has occurred, it represents less than 0.5% (see Supporting Information). The mechanism of the sulfinyl/carbonyl exchange disclosed here has not been established yet. It might involve the formation of the corresponding sulfinyl carboxylate intermediates 8 via addition of the carboxylic acids 3 to sulfinylamides 5 (Scheme 4). Then the liberated amines 1 add competitively to the sulfinyl (kSO) and carbonyl group (kCO), equilibrating back with 5 or producing amides 4. This would explain why bulky aliphatic acids and electron-rich benzoic acids are producing amides more slowly. It explains also why sulfinyl amides derived from electron-poor sulfinyl acids such as 4-nitrobenzenesulfinic acid and triflic acid did not generate any carboxamide. In the absence of a carboxylic acid, with/without DMAP, external amines do not exchange with those of the sulfinylamides (70 °C, 12 h). However, they do exchange in the presence of a carboxylic acid. With/without DMAP, EtOH does not react with 5ac (70 °C, 12 h). In the presence of 3-phenylpropionic acid 3A, a mixture of ethyl sulfinic ester 9a and amide 4aA is obtained (70 °C, 3 h). EtOH competes with amine 1a for the attack to the sulfinyl moiety. With i-PrOH no sulfinic ester is formed, only amide 4aA is obtained. In contrast, when heating B

dx.doi.org/10.1021/ol403508j | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Table 2. One-Pot Amidification of Carboxylic Acids 3 with Amines 1a

a

Amines 1: 0.6 M in CHCl3, yield of amide 4 after purification. bTime for reaction completion (TRC) after the addition of R3COOH: 2 h. cTRC after the addition of R3COOH: 3 h. dTRC after the addition of R3COOH: 4 h. eTRC after the addition of R3COOH: 6 h. fTRC after the addition of R3COOH: 8 h. gTRC after the addition of R3COOH: 10 h. hTRC after the addition of R3COOH: 16 h. iTRC after the addition of R3COOH: 24 h.

■

Scheme 4. Possible Mechanism for the Sulfinyl/Carbonyl Exchange

ASSOCIATED CONTENT

S Supporting Information *

Experimental procedures, spectra data, characterization data, and copies of 1H and 13C NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: Pierre.Vogel@epfl.ch. Author Contributions ‡

These authors contributed equally.

Notes

The authors declare no competing financial interest.

■

prop-2-enesulfinyl amide 5ac, i-PrOH with pivalic acid 3I slow formation of isopropyl sulfinic ester 9b and pyrrolidine is observed. In the presence of 1 equiv of water the yield in 4aA for reaction 3A + 5ac drops to 40%. At this stage of our studies we cannot exclude alternative mechanisms. One of them could be the formation of carboxylic anhydrides (R3CO)2O resulting, for instance, from the reaction of sulfinyl carboxylates 8 with the carboxylic acid 3. At 20 °C, 3phenylpropionic acid anhydride reacts with pyrrolidine to give 3A + 4aA. We cannot exclude an intramolecular 1,3-transfer of the amino moiety in intermediate 7 onto its carbonyl group. If this mechanism should prevail it implies that the amino moiety of 7 can exchange with external amines. Without the amine, acid 3A did not react with 2c (1 equiv) at 20 °C. When Et3N (1 equiv) was added to this mixture, sulfinyl carboxylate 8Ac formed together with products of decomposition10 of 2c. Then the addition of 1a (1 equiv) generated sulfinylamide 5ac and acid 3A. After this mixture was heated to 70 °C, amide 4aA formed in 62% yield, only. This procedure is lower yielding than in the case of first generating the sulfinylamide. In summary, an efficient and mild method has been developed for the one-pot, direct amidification of carboxylic acids that is applicable to primary and secondary amines, including the tert-butyl ester of α-amino acids. Aliphatic and aromatic carboxylic acids bearing unprotected alcohol, phenol, or ketone moieties can be used, including pivalic acid and benzylcarbamates of α-amino acids. Protected dipeptides have been obtained without α-epimerization of the carboxamides.

ACKNOWLEDGMENTS This work was supported by the European Community’s 7th Framework Program [FP7/2007-2013] under EC-GA No. 256986 PANACREAS, and the SCIEX program (Switzerland). Dedicated to Professor Inmaculada Robina, University of Seville, as acknowledgment of her fruitful collaboration.

■

REFERENCES

(1) For example: (a) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471−479. (b) Orliac, A.; Gomez Pardo, D.; Bombrun, A.; Cossy, J. Org. Lett. 2013, 15, 902−905. (c) Lanigan, R. M.; Starkov, P.; Sheppard, T. D. J. Org. Chem. 2013, 78, 4512−4523 and references cited therein. (d) Yao, H.; Tang, Y.; Yamamoto, K. Tetrahedron Lett. 2012, 53, 5094−5098. (e) Pirrung, M. C.; Zhang, F.; Ambadi, S.; Ibarra-Rivera, T. R. Eur. J. Org. Chem. 2012, 4283−4286. (f) Allen, C. L.; Chhatwal, A. R.; Williams, J. M. J. Chem. Commun. 2012, 666−668. (g) Pineda, A.; Gomez, L.; Balu, A. M.; Sebastian, V.; Ojeda, M.; Arrueba, M.; Romero, A. A.; Santamaría, J.; Luque, R. Green Chem. 2013, 15, 2043−2049. (h) Monks, B. M.; Whiting, A. In Sustainable Catalysis: Challenges and Practices for the Pharmaceutical and Fine Chemical Industries; Dunn, P. J., Hii, K. K., Krische, M. J., Williams, M. T., Eds.; J. Wiley & Sons, Inc., Hoboken, NJ, 2013; pp 89−110. (i) Houlding, T. K.; Tchabanenko, K.; Rahman, M. T.; Rebrov, E. V. Org. Biomol. Chem. 2013, 11, 4171−4177. (j) Mahe, O.; Desroches, J.; Paquin, J.-F. Eur. J. Org. Chem. 2013, 4325−4331. (k) Liu, S.; Yang, Y.; Liu, X.; Ferdousi, F. K.; Batsanov, A. S.; Whiting, A. Eur. J. Org. Chem. 2013, 5692−5700. (l) Fuse, S.; Mifune, Y.; Takahashi, T. Angew. Chem., Int. Ed. DOI: 10.1002/anie.201307987.

C

dx.doi.org/10.1021/ol403508j | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

(2) Zambron, B. K.; Dubbaka, S. R.; Markovic, D.; Moreno-Clavijo, E.; Vogel, P. Org. Lett. 2013, 15, 2550−2553 and references cited therein. (3) In the presence of SOCl2 as the catalyst reaction Y-NSO + RCOOH → RCONHY + SO2 has been realized on heating: Zhu, S.; Xu, B.; Zhang, J. J. Fluorine Chem. 1995, 74, 203−206. (4) Amides have been obtained by reaction of sulfinylamides with carboxylic anhydrides and acyl chlorides: (a) Isola, M. Tetrahedron Lett. 1982, 23, 1381−1384. (b) Dua, D. H. J. Org. Chem. 1991, 56, 4− 6. (c) Cogan, P. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268− 269. (d) Wipf, P. Helv. Chim. Acta 2002, 85, 3478−3488. (e) Alamanna, R. Tetrahedron Lett. 2009, 50, 4188−4190. And other forms of activated carboxylic acids; for example: (f) Gu, Z.; Zakarian, A. Angew. Chem., Int. Ed. 2010, 49, 9702−9705. (5) (a) Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 5446− 5448. (b) Wu, X.-Y.; Stockdill, J. L.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 4098−4100. (c) Chatterjee, J.; Gilon, C.; Hoffman, A.; Kessler, H. Acc. Chem. Res. 2008, 41, 1331−1342. (6) (a) Yuan, Y.; Chen, J.; Wan, Q. A.; Wilson, R. M.; Danishefsky, S. J. Biopolymers 2010, 94, 373−384. (b) Rao, Y.; Li, X. C.; Danishefsky, S. J. J. Am. Chem. Soc. 2009, 131, 12924−12926. (c) Wang, P.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 17045−17051. (7) Crich, D.; Sasaki, K. Org. Lett. 2009, 11, 3514−3517. (8) Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams, L. J. J. Am. Chem. Soc. 2003, 125, 7754−7755. (9) (a) Crich, D.; Sana, K.; Guo, S. Org. Lett. 2007, 9, 4423−4426. (b) Talan, R. S.; Sanki, A.; Sucheck, S. J. Carbohydr. Res. 2009, 344, 2048−2050. (c) Chen, W.; Shao, J.; Hu, M.; Yu, W.; Giulianotti, M. A.; Houghten, R. A.; Yu, Y. Chem. Sci 2013, 4, 970−976. (10) Tillet, T. G. In The Chemistry of Sulphinic Acids, Esters and Their Derivates; Patai, S., Ed.; WILEY-VCH: Chichester, 1990; pp 603−622. (11) Harmata, M.; Zheng, P. G.; Huang, C. F.; Gomes, M. G.; Ying, W. J.; Ranyanil, K.; Balan, G.; Calkins, N. L. J. Org. Chem. 2007, 72, 683−685. (12) Pickersgill, I. F.; Marchington, A. P.; Rayner, C. M. J. Chem. Soc., Chem. Commun. 1994, 22, 2597−2598. (13) Harmata, M.; Zheng, P. G.; Huang, C. F.; Gomes, M. G.; Ying, W. J.; Ranyanil, K.; Balan, G.; Calkins, N. J. Org. Chem. 2007, 72, 683− 685. (14) Ohoka, M.; Kojitani, T.; Yanagida, S.; Okahara, M.; Komori, S. J. Org. Chem. 1975, 40, 3540−3544. (15) Piggott, A. M.; Karuso, P. Tetrahedron Lett. 2007, 48, 7452− 7455. (16) Prop-2-enesulfinyl chloride was prepared from allyltrimethylisilane and thionyl chloride; for details see Supporting Information. (17) Varela-Alvarez, A.; Markovic, D.; Vogel, P.; Sordo, J. A. J. Am. Chem. Soc. 2009, 131, 9547−9561.

D

dx.doi.org/10.1021/ol403508j | Org. Lett. XXXX, XXX, XXX−XXX